Delivery devices and methods with collimated gas stream and particle source

ABSTRACT

Delivery devices, methods and systems are provided for the delivery of particles into a biological tissue. The device includes a gas source comprising a gas or capable of selectively producing a gas; a first particle source comprising a first plurality of particles; a first collimator fluidly connected with the gas source and adapted to form a collimated stream of the first plurality of particles entrained in the gas. The device also includes a tissue-interfacing surface adapted to interface with a surface of the tissue and orient the first collimator with the tissue such that the collimated stream of the first plurality of particles will penetrate the tissue in a direction substantially perpendicular to the surface of the tissue.

FIELD

The present disclosure is generally in the field of the administrationof substances, such as drugs, into a biological tissue, and in certainembodiments more particularly relates to devices and methods for thetransdermal delivery of a drug to a patient.

BACKGROUND

Transdermal drug delivery is an area of interest, particularly as analternative to drug delivery via needle injection. Examples oftransdermal drug delivery include the use of transdermal patches tofacilitate the diffusion of a drug into the skin.

The stratum corneum provides the most significant barrier to diffusionof a topically applied drug into the body of a patient. The stratumcorneum is the top layer of the skin and varies in thickness fromapproximately ten to several hundred micrometers, depending on theregion of the body. It is composed of layers of dead, flattenedkeratinocytes surrounded by a lipid matrix, which together act as abrick-and-mortar system that is difficult to penetrate.

Most transdermal drug delivery applications utilize at least one of twomain pathways by which drugs can cross the skin and reach the systemiccirculation. Using the “transcellular pathway” drugs cross the skin bydirectly passing through both the phospholipids membranes and thecytoplasm of the dead keratinocytes that constitute the stratum corneum.Although this is the path of shortest distance, the drugs encountersignificant resistance to permeation. Using the “intercellular pathway”drug passes through the small spaces between the cells of the skin,making the route more tortuous. Although the thickness of the stratumcorneum is only about 20 μm, the actual diffusional path of mostmolecules crossing the skin is on the order of 400 μm. The 20-foldincrease in the actual path of permeating molecules greatly reduces therate of drug penetration.

Another transdermal drug delivery approach utilizes high velocity jetsto impart sufficient momentum to a drug form to cause the drug form tobreach the stratum corneum. Most commonly high velocity jet injectorsare liquid-based. Liquid-based high velocity jet injectors produceliquid jets composed of liquid solutions or colloidal suspensions ofdrug macromolecules to deliver the drug to the patient. The liquid jetvelocity may be in the range of 100 m/s to 150 m/s. The use ofliquid-based high velocity injectors has not achieved wide acceptancedue to various challenges including: splashing, which riskscontamination and results in drug waste; pain and bruising due to lackof control over liquid penetration; high energy requirements; slowdelivery rates; usability challenges and operational skill requirements,which militate against the high reproducibility required of a drugdelivery device; and formulation challenges caused by jettingconstraints such as viscosity and surface tension.

Accordingly, it would be desirable to provide new methods, devices, andsystems for delivering drugs to patients.

SUMMARY

In one aspect, a delivery device is provided for the delivery ofparticles into a biological tissue. The device includes a gas sourcecomprising a gas or capable of selectively producing a gas; a firstparticle source comprising a first plurality of particles; a firstcollimator fluidly connected with the gas source and adapted to form acollimated stream of the first plurality of particles entrained in thegas. The device also includes a tissue-interfacing surface adapted tointerface with a surface of the tissue and orient the first collimatorwith the tissue such that the collimated stream of the first pluralityof particles will penetrate the tissue in a direction substantiallyperpendicular to the surface of the tissue.

In another aspect, a method is provided for delivering particles into abiological tissue. The method includes delivering a pressurized gas intoa collimator to produce a stream of gas; and then releasing a firstplurality of particles into the stream of gas to produce a collimatedstream of the first plurality of the particles entrained in the gas. Themethod further includes delivering the first plurality of particlesthrough a surface of the tissue in a direction substantiallyperpendicular to the surface of the tissue.

In yet another aspect, a drug delivery system is provided for deliveringa drug into a biological tissue. The system includes a particle deliverydevice for the delivery of particles into a tissue that includes a gassource comprising a gas; a first particle source comprising a firstplurality of particles; a first collimator fluidly connected with thegas source and adapted to form a collimated stream of the firstplurality of particles entrained in the gas; and a tissue-interfacingsurface adapted to interface with a surface of the tissue and align thefirst collimator with the tissue such that the collimated stream of thefirst plurality of particles will penetrate the tissue in a directionsubstantially perpendicular to the surface of the tissue. The systemalso includes a drug-delivery patch comprising a drug-permeabletissue-interfacing surface, a drug-impermeable backing layer, and a drugcontained between the tissue-interfacing surface and the backing layer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view, illustrating a drug delivery device inaccordance with one or more embodiments of the present disclosure.

FIG. 2 is an exploded perspective view, illustrating a drug deliverydevice in accordance with one or more embodiments of the presentdisclosure.

FIG. 3 is a section view, illustrating a drug delivery device inaccordance with one or more embodiments of the present disclosure.

FIG. 4 is a detail view, illustrating a cartridge for a drug deliverydevice in accordance with one ore more embodiments of the presentdisclosure.

FIG. 5 is an exploded perspective view, illustrating a drug deliverydevice in accordance with one or more embodiments of the presentdisclosure.

FIG. 6 is a detail view, illustrating a cartridge for a drug deliverydevice and a particle-release tape in accordance with one or moreembodiments of the present disclosure.

FIG. 7 is a section view, illustrating a drug delivery device includinga particle-release tape in accordance with one or more embodiments ofthe present disclosure.

FIG. 8 is a section view, illustrating the delivery of particles in acollimated stream of gas into a tissue in accordance with one or moreembodiments of the present disclosure.

DETAILED DESCRIPTION

New devices, methods, and systems are provided for the delivery drugsand other types of particles into tissue. In some embodiments, drug orparticle delivery is achieved by directing a plurality of collimated gasstreams at a tissue to form pores in the tissue to allow for the passageof the drug or other particle therethrough, such as for local orsystemic drug delivery. The collimation of the drug particlesadvantageously enables excellent control of the x, y, and zdistribution/penetration of the substances, thereby beneficiallyproviding no/minimal pain and tunable and uniform drug particlemomentum. In certain embodiments, the pores are formed by the momentumof the gas molecules in the collimated gas stream striking the tissue.Poration of the tissue may be enhanced by collisions of drug or otherparticles against the tissue, thereby allowing the drug or otherparticles to penetrate the surface, or outer layers, of the tissue.

Devices, methods, and systems are further provided for producingsupersonic collimated particle streams that maintain a beam diameter ofless than about 100 μm or less than about 50 μm over a length of about 1cm or more. Advantageously, in some embodiments, such devices methodsreduce or eliminate recoil/splashing, pain, and bruising associated withother needleless injection techniques. Such devices, methods, andsystems, in some embodiments, also provide increased control andreliability of drug delivery and reduce the operational skill requiredto perform needleless drug injection. This, in turn, advantageously canpromote more precise and accurate drug dosing.

The devices, systems, and methods described herein may be used fortargeted delivery of therapeutic, diagnostic, or other substances intoor through a variety of types of tissues or biological barriers,including suitable cells, tissues, or organs, including the skin orparts thereof, mucosal tissues, vascular tissues, lymphatic tissues, andthe like. In other embodiments, the target cells or tissues may be invarious animals, plants, insects, or other organisms. The tissue may bein humans or other mammals. For instance, a drug or other substance maybe delivered through the stratum corneum, and into underlying dermaltissues. The tissue may be a biological tissue of a patient in need of adrug. The patient may be a human, cattle, sheep, horse, pig, dog, cat,or other mammal, for example.

The devices and methods described herein may further include one or moreof the device features and techniques described in U.S. patentapplication Ser. No. ______, entitled “Drug Delivery Devices and Methodswith Collimated Gas Stream and Release-Activatable Tape” and in U.S.patent application Ser. No. ______, entitled “Drug Delivery Devices andMethods with Collimated Gas Stream and Drug Reservoir,” which are filedconcurrently herewith and which are incorporated by reference in theirentirety.

I. Drug Delivery Devices

Drug delivery devices, such as for transdermal drug delivery, aredisclosed. In one aspect, the drug delivery device includes a gas sourcewhich contains or produces a pressurized gas. The drug delivery devicealso includes one or more collimators that are fluidly connected withthe gas source. Each of the collimators may be adapted to form aplurality of collimated gas streams comprising the gas. The device mayfurther include a skin interfacing surface that is adapted to mate withthe skin (or other tissue surface) and align the collimator with theskin such that the plurality of collimated gas streams penetrate theskin in a direction substantially perpendicular to the skin.

In another aspect, a drug delivery device is provided that includes adrug reservoir containing a drug in solid particle or liquid form, a gassource for storing or producing a pressurized gas, and a collimatorcomprising a plurality of conduits. Each of the plurality of conduitsmay include an inlet, an outlet and a drug port between the inlet andthe outlet. Each drug port is fluidly connected (or is operable tobecome fluidly connected) with the drug reservoir, and the inlet end ofeach of the plurality of conduits is fluidly connected (or is operableto become fluidly connected) with the gas source.

In certain embodiments, the drug delivery device is configured toproduce collimated gas streams having a sufficient velocity to penetratehuman stratum corneum. For example, the drug delivery device may beconfigured to produce collimated gas streams having a velocity of about100 to about 1500 m/s. In certain embodiments, each of the collimatedgas streams has a diameter of about 5 μm to about 500 μm at a distanceof about 0.5 mm to 10 mm from the outlet of the collimator.

Effective collimation may be achieved by delivering a propellant into aconduit and controllably introducing or metering the particles into thechannel such that the propellant propels the particles into the barrier.The shape of the channel or conduit may result in a collimated (i.e.,focused) flight of the propellant and particles to the barrier. Theparticles may then be introduced into the propellant stream from one ormore material inlet ports. The propellant may enter the channel at ahigh velocity. Alternatively, the propellant may be introduced into thechannel at a high pressure, and the channel may include a constriction(e.g., de Laval or other converging/diverging type nozzle) forconverting the high pressure of the propellant to high velocity. In sucha case, the propellant is introduced at a port located at a proximal endof the channel (i.e., near the converging region), and the materialports are provided near the distal end of the channel (at or furtherdown-stream of a region defined as the diverging region), allowing forintroduction of material into the propellant stream. It has beendemonstrated that a propellant and the material flow pattern can remainrelatively collimated for a distance of up to 10 millimeters. Forexample, the stream does not deviate by more than about 20 percent, andpreferably by not more than about 10 percent, from the width of the exitorifice for a distance of at least 4 times the exit orifice width.

In certain embodiments, the collimator may include a plurality ofconduits. Each conduit may have an inlet and an outlet. Each of theconduits may have a venturi located between the inlet and the outlet. Incertain embodiments, each conduit has an expansion neck region whichexpands the gas stream downstream of the inlet. For example, anexpansion neck region may be provided at the exit of the venturi.

In some embodiments, the drug delivery device releases a drug from thedrug source into the collimated gas streams such that the drug becomesentrained in each gas stream and is transported into the skin in adirection substantially perpendicular to the skin. For example, each ofthe conduits may have a drug port (i.e., an opening) between the inletand outlet of the conduit, and the drug port may be fluidly connectedwith the drug source. In certain embodiments, the drug port isdownstream of the venturi. In some embodiments, the drug delivery deviceincludes a rupturable membrane between the drug source and thecollimator. For example, the rupturable membrane may seal the drug portuntil the membrane is ruptured. Rupture of the rupturable membrane maybe controlled by the operator of the device.

When the material port is placed downstream of the venturi or downstreamof the location at which the high velocity stream of gas is established,the particles may be pushed into the high velocity gas stream by apressure differential (e.g., Bernoulli's force). For example, based onBernoulli's equation, if particles are contained in an open reservoiradjacent to a high velocity gas stream of 750 m/s, a pressure differenceof about 2.2 atm is generated and pushes the particles into the gasstream.

The drug delivery device may include a standoff between the collimatorand the skin interfacing surface such that a gap is provided between theoutlets of the collimator and the skin when the skin interfacing surfaceis placed against the skin. For example, the standoff may create a gapof about 0.5 to about 10 mm.

In some embodiments, the collimator and drug source are provided in theform of a removable cartridge. The drug delivery device may include oneor more cartridge receivers for receiving one or more removablecartridges. The cartridge may be inserted into the receiver fordelivering drugs contained in the cartridge into a patient's skin. Thecartridge, which may be depleted of drug, may thereafter be removed andreplaced. In some embodiments, the drug delivery device includes aplurality of cartridge receivers for receiving multiple cartridges. Incertain embodiments, each cartridge may contain an amount of the drugsuitable for an individual dosage.

An exemplary embodiment of a drug delivery device 10 is illustrated inFIGS. 1-3. The drug delivery device 10 includes a gas source housing 12and a cartridge housing 14. The gas source housing 12 may be dimensionedto fit comfortably in a hand when the fingers are wrapped around thecylindrical sidewall of the gas source housing 12. The cartridge housing14 is located at one end of the drug delivery device 10. As illustratedin FIG. 2, the cartridge housing 14 may be located at the end of thedrug delivery device 10 opposite a push switch 16. Although the pushswitch 16 is illustrated at one end of the drug delivery device 10, thepush switch 16 can also be located elsewhere on the device, such as onthe cylindrical sidewall of the gas source housing 12. The cartridgehousing 14 includes at one end a tissue interfacing surface 22. Thetissue interfacing surface 22 may be a generally planar surface that isadapted to align the gas streams in a substantially perpendiculardirection to the tissue surface mating with the tissue interfacingsurface 22.

As illustrated in FIG. 3, the gas source housing 12 also surrounds a gassource 18, which contains or generates a pressurized gas. In theembodiment of FIG. 3, the pressurized gas is selectively delivered toone of three cartridges 34 via a corresponding gas delivery conduit 20.Gas delivery may be actuated by pressing the push switch 16. A powersource 32 and a controller 33 may then selectively actuate a valve tocontrol the flow of pressurized gas from the gas source 18 through thedesired gas delivery conduit 20. For example, the controller 33 maysequentially activate one of three control valves with each press of thepush switch 16. In embodiments in which gas is generated on-board thedrug delivery device 10, the controller 33 may also actuate the processthat generates the gas.

The cartridge housing 14 includes three cartridge receivers forreceiving the three cartridges 34. The cartridges 34 may be removableand replaceable, such that the new cartridges can be inserted into thecartridge receivers once the original cartridges 34 are expended. Tothis end, the cartridge housing 14 may comprise cartridge removaldevices, e.g., spring-loaded push rods, to facilitate the removal ofexpended cartridges from the cartridge housing 14. Although slots forthree cartridges 34 is illustrated in the present embodiment, it shouldbe noted that the device could be designed to accommodate one, two,four, or any number of cartridges 34. The cartridge housing 14 includesa standoff 36 which provides a gap of distance x between the end of thecartridges 34 and tissue interfacing surface 22. In some embodiments,the distance x of the gap may between about 0.1 and about 5 mm.

Gas Source

The device may include a gas source which contains or produces apressurized gas. For example, gas pressures greater than or equal toabout 0.5 MPa would be sufficient entrain and drive the collimatedgas/drug from the drug delivery device. The pressurized gas may bevarious gases, including, but not limited to air, carbon dioxide,nitrogen, or oxygen. In some embodiments, pressure is generatedon-board. For example, gas may be generated on-board by a chemical orelectro-chemical reaction. One example of such a system includes anelectrochemical cell that breaks down water into hydrogen gas (H₂) andoxygen gas (O₂). The water source could be in liquid form or stored in ahydrogel on-board the device. Another example is a system that relies onphase transformation, such as boiling of water to generate steam. Stillother examples include systems that utilizes a chemical reaction ordecomposition, for instance, sodium azide decomposition into sodium andnitrogen gas (N₂) or the reaction of calcium carbonate with an acid toyield carbon dioxide gas (CO₂). In some embodiments, the gas is providedin a pressurized vessel and is delivered, such as through a valve, tothe collimator when needed. For example, the valve may be actuated bypressing a push switch on the drug delivery device. In some embodiments,the pressure may be generated by a mechanical device, such as a pump.

Collimator

The device may include a collimator for producing a plurality ofdiscrete collimated gas streams. The term “collimated” as used hereinrefers to a stream of gas, which may include solid particles or liquidentrained therein, that maintains a well-defined and substantiallyconstant diameter over a desired, useful distance, including whenunconstrained by a sidewall structure. For example, the collimator maymaintain a diameter of about 5 μm to about 500 μm over a distance ofabout 0.5 mm to about 10 mm. The collimator and drug delivery device maybe configured and arranged to produce gas streams having a velocity ofabout 100 to about 1500 m/s.

An exemplary collimator 40 is illustrated in FIG. 4. The collimator 40includes a plurality of conduits, which may be etched, cut or milled onthe surface of a plate. Although the conduits are illustrated as openchannels in FIG. 4, it should be appreciated that the channels arebounded by a top layer when used. The top layer may be integral with thecartridge 34 or it may be a surface of the cartridge receiver that mateswith the collimator 40 when the cartridge 34 is received in thecartridge receiver. Each of the conduits has an inlet 44 at one end ofthe cartridge 34 and an outlet 46 at the other end of the cartridge 34.A venturi 48 is provided in each conduit between the inlet 44 and theoutlet 46. An expanding neck region 50 is provided immediatelydownstream of each venturi 48. As the pressurized gas passes through theventuri 48, expands into the expanding neck region 50, and exits throughoutlet 46 well-defined, collimated gas streams are formed. The venturiis designed so as to produce an exit pressure of approximately 1atmosphere, i.e. the pressure inside the free jet is substantially equalto atmosphere, so as to not produce an expanding or contracting jet. Adrug port 52 is provided downstream of the venturi 48 for releasing adrug from drug source 42 and entraining the drug in the gas stream.

Although the collimator 40 has been described with reference to drugdelivery, it should be noted that the collimator may be used to deliverother liquids or particles into a tissue as is described in greaterdetail subsequently.

Drug/Particle Source

Drugs or other particles may be provided on-board the drug deliverydevice in a drug or particle source. In some embodiments, the drugs orparticles are contained in a reservoir. As previously described, a drugport may be provided between the drug source and the collimator forallowing release of the drug therethrough.

Release of the drug may be controlled by a rupturable membrane thatseals the drug port. The rupturable membrane may be ruptured by thepressure change caused by the pressurized gas being fed through thecollimator. Alternatively, the rupturable membrane may be ruptured byactuation of another element. For example, the rupturable membrane maybe ruptured by electrothermal ablation, mechanical puncturing (e.g.,with a scepter), heating (e.g., melting the membrane), chemicalreaction, or volumetric expansion of the reservoir contents

Other release devices may be provided to control the release of the drugfrom the drug reservoir. For example, an electric charge or movablecover may be used to prevent the release of the drug through the drugport until such later time that release is desired and the releasedevice is actuated.

In other embodiments, the drug may be released from arelease-activatable tape. For example, the release-activatable tape mayhave the drug disposed on the tape. In some embodiments, therelease-activatable tape may be used to release other types of solidparticles or liquids. The release-activatable tape may comprise aUV-sensitive, heat-sensitive, or electrical-sensitive material. Thedevice may also include a controller that is adapted to actuate therelease of the drug or other particle from the release-activatable tape.In some embodiments, the controller is adapted to actuate the release ofthe drug from the release-activatable tape after the pressurized gas hasbegun to pass through the collimator.

In some embodiments, the release-activatable tape is positioned withinor adjacent to the first collimator. For example, as illustrated in FIG.6, the cartridge 60 may include a collimator 62 having a plurality ofconduits or channels, which may be etched, cut or milled on the surfaceof a plate. Although the conduits are illustrated as open channels inFIG. 6, it should be appreciated that the channels are bounded by a toplayer when used. The top layer may be integral with the cartridge 60.Each of the conduits has an inlet 66 at one end of the cartridge 60 andan outlet 72 at the other end of the cartridge 60. A venturi 64 isprovided in each conduit between the inlet 66 and the outlet 72. Anexpanding neck region 68 is provided immediately downstream of eachventuri 64. As the pressurized gas passes through the venturi 64,expands into the expanding neck region 68, and exits through outlet 72well-defined, collimated gas streams are formed. The venturi is designedso as to produce an exit pressure of approximately 1 atmosphere, i.e.the pressure inside the free jet is substantially equal to atmosphere,so as to not produce an expanding or contracting jet. A particle-releasetape 74 is provided adjacent to the channels downstream of the venturi64 for releasing a drug or other particle and entraining the drug orother particle in the gas stream. A controller 65 may selectivelyactuate the release of the particles from the particle-release tape 74.

As illustrated in FIG. 7, the particle-release tape 74 may be positionedwithin or adjacent to the channel 78 of the collimator 62. In theillustrated embodiment, the particle-release tape 74 is situated withina relief that is etched, cut or milled in a surface of the collimatortop plate 76. As such, the particle-release tape 74 faces the channel 78between the venturi and the outlet 72. When the particle-release tape 74is actuated to release the particles contained in the particle releasetape 74 (e.g., by the application of heat, UV, or electrical energy tothe tape), the particles are released into the channel 78 where they areentrained in the gas flowing through the channel 78.

Particles

The device may deliver various types of solid particles and liquids. Forexample, the device may deliver drugs, tissue abrasive particles,cosmetic particles, nutritional or nourishing particles, or tissuemarking particles into the biological tissue.

As used herein, the term “drug” refers to any chemical or biologicalmaterial or compound suitable for administration by the methodspreviously known in the art and/or by the methods taught in the presentdisclosure, that induces a desired biological or pharmacological effect,which may include but is not limited to (1) having a prophylactic effecton the organism and preventing an undesired biological effect such aspreventing an infection, (2) alleviating a condition caused by adisease, for example, alleviating pain or inflammation caused as aresult of disease, and/or (3) either alleviating, reducing, orcompletely eliminating the disease from the organism. The effect may belocal, such as providing for a local anaesthetic effect, or it may besystemic. The drug may be a therapeutic or prophylactic agent. Forexample, the drug may be a vaccine. The drug may be formulated in asubstantially pure form or with one or more excipients known in the art.The excipient material may be homogenously mixed with the drug orheterogenously combined with the drug. For example, the drug may bedispersed in an excipient (matrix) material known in the art, or may beincluded in a core or coating layer in a multi-layered structure with anexcipient material. In some embodiments, the excipient material mayfunction to control in vivo release of the drug, for example to providetimed release (e.g., controlled or sustained release) of the drug.

The device may also contain and deliver tissue abrasive particles. Thetissue abrasive particles may be any particles suitable for abrading orpenetrating the surface of a biological tissue after delivery from thedevice and impinging the biological tissue to form, at leasttransiently, microconduits in the surface of the biological tissue. Inone embodiment of the invention, solid, persistent particles that do notdissolve within the tissue after impinging, such as particles comprisedof aluminum oxide, also referred to as “alumina,” are used to formsuitable microconduits. Particles suitable for use in an embodimentinclude solid phase particles comprised of biocompatible substances thatexist in the liquid state at normal physiologic tissue temperatures, forexample normal human body temperature. In one embodiment, the particleshave a melting point less than about 33° C. For example, the tissueabrasive particles may comprise frozen water. Such solid phase particlesimpinge onto a localized region of tissue surface, and enter into thetissue, creating microconduits. Such solid phase particles may meltwithin the tissue, and the resulting liquid may with tissue interstitialfluid.

The device may also contain and deliver nourishing or nutritionalparticles. The nourishing or nutritional particles may be any particlessuitable for promoting or maintaining the viability of the cells of thebiological tissue. Such particles may include vitamins, minerals, andother non-drug particles that contain nutrients.

The device may also contain and deliver cosmetic particles. The cosmeticparticles may be any particles suitable for providing a cosmetic effectto the biological tissue when delivered to the tissue. For example, theparticles may be particles that diminish the appearance of wrinkles,that provide color or alter the coloration of the biological tissue, orthat create or reduce localized swelling.

The device may also contain and deliver tissue marking particles. Thetissue marking particles may be any particles suitable for marking atissue for identification, whether such an identification may be madevisually, with or without the assistance of technology (e.g., an imagingtechnology). For example, the particles may comprise an ink or dye orthe particles may contain an agent that is visible or capable of imagingwith an imaging technology, such as X-Ray, IR, MRI, CT, or ultrasound.

In certain embodiments, the solid particles have a volume averagediameter of about 0.1 to about 250 microns. In a preferred embodiment,the solid particles have a volume average diameter equal to or less than⅕ the width of the conduit or channel, and even more preferably equal toor less than 1/10 the of the width of the conduit or channel.

II. Methods of Administration of Drugs or Other Substances

Methods are provided for the needleless injection of gas streams anddrugs or other particles into human or animal tissues. Although many ofthe examples herein are described in the context of drug delivery intoskin, the drug delivery devices disclosed herein may be used to deliverdrugs and/or other particles into other tissue surface. For example, thedrug delivery device and methods may also be used to deliver drugs intoophthalmic or mucosal tissues. In ophthalmic applications, the velocityof the collimated streams may be controlled to deliver the drugs at adepth sufficient to deliver the drugs into the vitreous humor.

In one aspect, a method is provided for delivering a substance into ahuman or animal tissue. The method includes delivering a pressurized gasinto a collimator to produce a plurality of collimated streams of gas;penetrating the tissue with the plurality of collimated streams of gasto produce a plurality of pores in the tissue; and delivering thesubstance into the tissue via the plurality of pores. For example, themethod may be used to deliver a drug into the tissue. The drug or othersubstance may be in the form of solid particles having a volume averagediameter of about 0.1 to about 250 microns. In a preferred embodiment,the solid particles have a volume average diameter equal to or less than⅕ the width of the conduit or channel, and even more preferably equal toor less than 1/10 the of the width of the conduit or channel.

The collimator may comprise a plurality of conduits, and the collimatedstreams of gas may be produced by expanding the pressurized gas througha venturi in each of the plurality of conduits. Each of the plurality ofcollimated gas streams may have a diameter of a about 5 μm to about 500μm from the outlet of the conduit. Each of the plurality of collimatedstreams of gas may have a velocity of about 100 to about 1500 m/s. Thepressurized gas may be provided from an on-board gas source. In someembodiments, the gas may be generated on-board.

In some embodiments, the method includes entraining the substance, suchas a drug, in each of the plurality of collimated streams of gas. Incertain embodiments, the method the plurality of collimated streams ofgas are established before the substance is entrained in the pluralityof collimated streams of gas. The substance may be entrained in thecollimated streams by rupturing a membrane to release the substance intoeach of the plurality of collimated streams of gas. The entrainment ofthe substance into the collimated gas stream may occur essentiallyimmediately following generation of the collimated gas stream, or may beoccur a short time thereafter, for example, to allow for stabilizationof the stream.

To use, the tissue interfacing surface of the device may be placedagainst a desired tissue surface and then the gas source may be actuatedto deliver the pressurized gas to the collimator. For example, thetissue interfacing surface may be placed against the skin or a mucosalsurface. Alternatively, in ophthalmic applications, the tissueinterfacing surface may be placed against the sclera. The gas source maybe actuated by pressing a push switch (such as illustrated in FIG. 3) oranother element to initiate the delivery of pressurized gas to thecollimator. In certain embodiments, pressing the push switch may alsoactuate rupturing of a rupturable membrane sealing the drug port.

As illustrated in FIG. 8, the delivery of a drug or other particles intoa tissue may be achieved by forming well-defined collimated streams ofparticles entrained in a carrier gas 88. The particles, being inwell-defined collimated streams, form (at least transiently)microconduits 94 in the tissue 92 upon striking the tissue and pass intothe tissue 92 through the formed microconduits 94.

In the illustrated embodiment, the skin-interfacing surface 90 of thedevice is placed against the tissue 92 (e.g., skin) such that thechannels 82 of the collimator 84 are aligned in a substantiallyperpendicular direction with respect to the tissue 92. The collimator 84is preferably configured such that the each stream of particles exitingan outlet 86 of the collimator 84 follows a well-defined, collimatedpath having a width of about 5 μm to about 500 μm between the outlets 86and the tissue surface 92. Each of the collimated streams of gas (andparticles entrained therein) may have a velocity of about 100 to about1500 m/s. The distance x between the outlets 86 of the collimator 84 andthe tissue 92 is preferably between about 0.5 mm and about 10 mm.

The device may also be used to deliver other substances into the tissue.For example, the foregoing devices may contain and be used to deliverporation enhancers, cosmetic particles, nutritional/nourishingparticles, and/or marking particles into a tissue.

In some embodiments, the device may deliver substances that enhanceporation of the tissue to facilitate the delivery of drugs into thetissue. For example, in any of the aforementioned methods, the devicemay be used to deliver abrasive particles into a tissue to form, atleast transiently, microconduits or pores in the tissue. A drug or othersubstance may thereafter be delivered into the tissue through themicroconduits. In an exemplary embodiment, the device may be used todeliver abrasive particles into the skin to form microconduits in thestratum corneum. A drug-containing delivery system, such as a patch, maythen be applied to the tissue site, and the drug may be delivered to thetissue site via the microconduits. Alternatively, the device may beconfigured to deliver abrasive particles and then another substance,such as a drug, to the tissue in sequence. In such an embodiment, theabrasive particles may be released into the collimator for a firstperiod of time and then the other substance, e.g., the drug, may bereleased into the collimator for a second, later period of time and passinto the tissue through the microconduits or pores formed by theabrasive particles.

III. Drug Delivery Systems

System for the delivery of drugs and other particles are also disclosed.In one aspect, the system includes a drug delivery device comprising agas source and one or more cartridge receivers. The system also includesone or more cartridges adapted to insert into the each of the cartridgereceiver. Each cartridge includes a collimator and a drug source. Thedrug source may contain a drug in solid particle or liquid form. Thecollimator may be adapted to form a plurality of collimated gas streamscomprising a drug entrained in a gas when the gas is fed to thecollimator from the gas source.

In some embodiments, each cartridge receiver or cartridge furtherincludes a manifold for delivering a gas from the gas source into thecollimator. Each collimator may include a plurality of conduits. Eachconduit may have an inlet, an outlet, and a venturi between the inletand the outlet. Each of the conduits may also have an expanding neckregion and a drug port between the inlet and outlet downstream of theventuri. The drug port is in fluid communication with the drug source.The drug source may be a drug reservoir containing a drug. In someembodiments, each cartridge may further include a rupturable membranebetween the collimator and the drug source. The rupturable membraneseals each of the drug ports.

In some embodiments, the drug delivery device further includes a tissueinterfacing surface that is adapted to mate with the desired tissuesurface and align first collimator with the tissue such that theconduits are aligned in a direction substantially perpendicular to thetissue when the cartridge is situated in the cartridge receiver. Thedrug delivery device may further include a standoff between the firstcollimator and the tissue interfacing surface when the first cartridgeis situated in the first cartridge receiver such that a gap is providedbetween the first collimator and a tissue surface when the tissueinterfacing surface is placed against the tissue surface. For example,the standoff may create a gap of about 0.5 mm to about 10 mm The drugdelivery device may be configured to produce a plurality of collimatedgas streams having a diameter of about 5 μm to about 500 μm at adistance of about 0.5 mm to about 10 mm from the first collimator. Insome embodiments, the drug delivery device is configured to producecollimated gas streams having a sufficient velocity to penetrate humanstratum corneum.

An exemplary drug delivery system is illustrated in FIG. 5. The systemincludes a drug delivery device 10 having a cartridge housing 14. Thecartridge housing 14 includes three cartridge receivers for receivingthree replaceable cartridges 34. The replaceable cartridges 34 may beinserted into the cartridge receivers of the cartridge housing and thenmay be removed from the cartridge housing after being expended. Althoughthree replaceable cartridges 34 and cartridge receivers are shown, thecartridge housing 14 may be made to accommodate any number of cartridges34.

Cartridges

As previously described, the drug delivery device may include removableand/or replaceable cartridges that contain the drug or other particles.Each cartridge may contain an amount of a drug sufficient for anindividual dosage. Each cartridge may also include a collimatorintegrally associated therewith.

An exemplary cartridge 34 is illustrated in FIG. 4. In the illustratedembodiment, the collimator 40 is in the form of a plate having aplurality of conduits formed therein. Although not shown, a top plate orother element may be placed over the top of the collimator to seal theopen tops of the conduits that are formed in the plate. The collimator40 is attached to a drug source 42. The drug source 42 may be areservoir containing a drug in solid particle or liquid form. Theconduits of the collimator 40 are fluidly connected with the drug source42 via drug ports 52 provided in the conduits downstream of the venturis48.

Another cartridge 60 is illustrated in FIGS. 6-7. In the illustratedembodiment, the collimator 62 is in the form of a plate having aplurality of conduits or channels formed therein. As illustrated in FIG.7, a collimator top plate 76 may be placed over the top of thecollimator 62 to seal the open tops of the conduits that are formed inthe plate and to support a particle-release tape 74 that is disposed ina relief of the collimator top plate 76. The particle-release tape 74therefore faces the channels 78 of the collimator 62.

In some embodiments, the cartridge may contain at least two differentsubstances. Each substance may be delivered into the collimator from asource such as a reservoir or a release-activatable tape. For example,the cartridge may include two or more reservoirs, each containing adifferent substance. Alternatively, the cartridge may include arelease-activatable tape comprising a first substance and a reservoircontaining a second substance. The cartridge may be adapted to releaseeach substance independently so that the substances can be delivered atdifferent times, e.g., successively.

In some embodiments, the two or more substances may each be a drug. Forexample, two or more drugs useful in a combination therapy may bedelivered to the tissue. In other embodiments, the cartridge may includeabrasive particles and a drug. The cartridge may be adapted to allow forthe independent delivery of the abrasive particles and the drug into thecollimator so that the abrasive particle may be expelled from thecollimator before the drug is delivered.

Patches

In some embodiments, a drug-delivery patch may be used in combinationwith the device to deliver a drug into the tissue through themicroconduits formed in the tissue by the device. The patch may includea drug-permeable tissue-interfacing surface, a drug-impermeable backinglayer, and a drug contained between the tissue-interfacing surface andbacking layer. The patch may include an adhesive suitable for adheringthe patch to the skin. The drug delivery patch may be applied to thetissue site treated with the device so that the drug contained in thepatch may diffuse through the drug-permeable tissue-interfacing surfaceof the patch and into the tissue.

It should be understood that the foregoing relates only to the preferredembodiments of the present application and that numerous changes andmodifications may be made herein without departing from the generalspirit and scope of the invention as defined by the following claims andthe equivalents thereof

1. A delivery device for the delivery of particles into a biologicaltissue comprising: a housing; a gas source comprising a gas or capableof selectively producing a gas; a first particle source comprising afirst plurality of particles; a first collimator fluidly connected withthe gas source and adapted to form a collimated stream of the firstplurality of particles entrained in the gas; and a tissue-interfacingsurface located at one end of the housing and adapted to interface witha surface of the tissue and orient the first collimator with the tissuesuch that the collimated stream of the first plurality of particles willpenetrate the tissue in a direction substantially perpendicular to thesurface of the tissue.
 2. The delivery device of claim 1, wherein thefirst plurality of particles comprise tissue abrasive particles.
 3. Thedelivery device of claim 1, wherein the first plurality of particlescomprise tissue marking particles, nourishing particles, nutritionalparticles, or cosmetic particles.
 4. The delivery device of claim 1,wherein the first plurality of particles comprise drug particles.
 5. Thedelivery device of claim 1, further comprising a second particle sourcecomprising a second plurality of particles; and wherein the firstcollimator is adapted to form a second collimated stream of the secondplurality of particles entrained in the gas.
 6. The delivery device ofclaim 5, wherein the delivery device is adapted to form the secondcollimated stream of particles after forming the first collimated streamof particles.
 7. The delivery device of claim 1, wherein the firstcollimator is adapted to form a plurality of collimated streams of thefirst plurality of particles entrained in the gas.
 8. The deliverydevice of claim 1, wherein the first collimator and the first particlesource are provided in a removable cartridge. Application No.:13/089,769 Filed: April 19, 2011 AMENDMENT AND RESPONSE TO OFFICE ACTION9. The delivery device of claim 5, wherein the first collimator, thefirst particle source, and the second particle source are provided in aremovable cartridge.
 10. The delivery device of claim 1, wherein thefirst collimator has an inlet end and an outlet end; and wherein thefirst particle source is positioned and configured to release the firstplurality of particles into the gas between the inlet end and the outletend of the first collimator.
 11. A method of delivering particles into abiological tissue comprising: delivering a pressurized gas into acollimator to produce a stream of gas; and then releasing a firstplurality of particles into the stream of gas to produce a collimatedstream of the first plurality of the particles entrained in the gas; anddelivering the first plurality of particles through a surface of thetissue in a direction substantially perpendicular to the surface of thetissue.
 12. The method of claim 11, wherein the first plurality ofparticles comprise drug particles.
 13. The method of claim 11, whereinthe first plurality of particles comprise abrasive particles.
 14. Themethod of claim 11, wherein the step of delivering the plurality ofparticles through the surface of the tissue forms a plurality ofmicroconduits in the surface of the tissue.
 15. The method of claim 14,further comprising: applying a drug-delivery patch to the tissue overthe plurality of microconduits, the drug delivery patch comprising adrug; and allowing the drug to diffuse into the tissue through theplurality of microconduits.
 16. The method of claim 15, wherein thedrug-delivery patch comprises drug-permeable tissue-interfacing surfaceand a drug-impermeable backing layer, and wherein the drug is containedbetween the tissue-interfacing surface and the backing layer.
 17. Themethod of claim 11, further comprising, after the step of delivering thefirst plurality of particles through the surface of the tissue,releasing a drug into the gas to produce a collimated stream of the drugentrained in the gas; and delivering the drug through the surface of thetissue in the direction substantially perpendicular to the surface ofthe tissue.
 18. The method of claim 11, wherein the first plurality ofparticles are released from a release-activatable tape having the firstplurality of particles disposed thereon.
 19. The method of claim 11,wherein the step of releasing the first plurality of particles into thegas comprises rupturing a rupturable membrane separating the firstplurality of particles from the collimator.
 20. A drug delivery systemfor delivering a drug into a biological tissue comprising: a particledelivery device for the delivery of particles into a tissue comprising:a housing; a gas source comprising a gas; a first particle sourcecomprising a first plurality of particles; a first collimator fluidlyconnected with the gas source and adapted to form a collimated stream ofthe first plurality of particles entrained in the gas; and atissue-interfacing surface located at one end of the housing and adaptedto interface with a surface of the tissue and align the first collimatorwith the tissue such that the collimated stream of the first pluralityof particles will penetrate the tissue in a direction substantiallyperpendicular to the surface of the tissue; and a drug-delivery patchcomprising a drug-permeable tissue-interfacing surface, adrug-impermeable backing layer, and a drug contained between thetissue-interfacing surface and the backing layer.
 21. The system ofclaim 20, wherein the first plurality of particles comprise tissueabrasive particles.